Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is one of intractable diseases and there are about 120 thousands patients with IBD in Japan. Nowadays, differential diagnosis between ulcerative colitis and Crohn's disease in a patient with IBD is mainly conducted by pathological features including specific appearance observed by barium enema, endoscope observation, presence or absence of epithelioid cell granuloma as well as clinical features including presence or absence of blood in stool and perianal lesions. Those criteria require endoscopy which invites large burden on the patient being diagnosed. A noninvasive and objective method for differential diagnosis of a patient with inflammatory bowel disease has been desired.
Immunoglobulin G (hereinafter, IgG) is a glycoprotein and is constituting about 75-85% of serum immunoglobulins in normal humans. As shown in FIG. 1, IgG is a symmetric molecule built of two identical H chains and two identical L chains.
IgG carries oligosaccharides in their Fc fragment and the oligosaccharide plays an important role in keeping the steric structure of IgG. In addition, the oligosaccharide affects the interaction between IgG and Fcγ receptor or effecter molecules such as complement. Sixteen IgG oligosaccharides shown in FIG. 2 have been known.
In healthy people, the relative rates among the 16 IgG oligosaccharides are approximately constant. However, the oligosaccharide balance is specific in patients with myeloma or rheumatoid arthritis (RA). For example, patients with rheumatoid arthritis have significantly increased levels of serum agalactosyl immunoglobulin G (IgG) which lacks terminal galactose in the IgG oligosaccharide. A method for diagnosing RA based on this finding has been proposed (non-patent literature 1) and methods for determining relative ratio of oligosaccharides (Patent Literature 1) and for detecting anti-agalactosyl IgG autoantibodies (CARF) in the sera (non-patent literature 2) have been developed. Although CARF correlates with disease activity of RA, it has been revealed that CARF does not necessarily reflect the amount of serum agalactsyl IgG.
Diagnosis based on IgG oligosaccharide alteration has been proposed for diagnosing AIDS condition (patent literature 2), hepatic diseases, malignant hypertension, immunoglobulin A nephropathy and diseases in children (patent literature 3). Especially, the increase of serum agalactosyl IgG has been reported in patients with inflammatory diseases (Non patent literature 3) and among the inflammatory diseases, the increase of serum agalactosyl IgG is significant in patients with autoimmune diseases. Acute phase cytokines such as TNF and IL6 have been suggested to play a role in the mechanism for the increase of agalactosyl IgG in a patient with such disease as above. However, the detail has not yet been revealed. It has been reported that agalactosyl IgG in the sera of patients with inflammatory bowel disease including Crohn's disease and ulcerative colitis is higher than that in the sera of healthy people. It has also been suggested that the amount of serum agalactosyl IgG correlates with C-reactive protein (CEP) and clinical activity (Non patent literatures 4 and 5). However, these reports were made on the ratio of agalactsyl IgG oligosaccharide in all serum IgG oligosaccharide fractions. No study has yet been reported on the correlation of the relationship between specific IgG oligosaccharides and IBD.
[Patent Literature 1] JP 8-220099 A
[Patent Literature 2] JP 7-209301 A
[Patent Literature 3] JP 8-82623 A
[Non Patent Literature 1] TAKARA BIO ONLINE CATALOGUE “Method for analyzing human IgG oligosaccharides using PALSTATION®” bio.takara.co.jp/catalog/catalog d.asp?C ID=C0730, searched and downloaded on Mar. 15, 2006.
[Non Patent Literature 2] Package insert of PICOLUMI® CA•RF, a diagnosing kit for the determination serum anti-agalactosy IgG antibodies
[Non Patent Literature 3] Thomas W. Rademacher et al., Springer Semin Immunopathol, Vol. 10, 231-249 (1998)
[Non Patent Literature 4] R Dube et al., Gut, Vol. 31, 431-434 (1990)
[Non Patent Literature 5] Mae F. G0 et al., J. Clin. Gastroenterol. Vol. 18, 86-87 (1994)